Multi-API Loading Prodrugs

ABSTRACT

The present invention accomplishes this by having multiple molecules of parent drugs attached to carrier moieties and by extending the period during which the parent drug is released and absorbed after administration to the patient and providing a longer duration of action per dose than the parent drug itself. Prodrug conjugates are suitable for sustained delivery of heteroaryl, lactam-amide-, imide-, sulfonamide-, carbamate-, urea-, benzamide-, acylaniline-, cyclic amide- and tertiary amine-containing parent drugs that are substituted at the amide nitrogen or oxygen atom with labile aldehyde-linked prodrug moieties. The carrier groups of the prodrugs can be hydrophobic to reduce the polarity and solubility of the parent drug under physiological conditions.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/335,405, filed Dec. 22, 2011, which claims the benefit of U.S.Provisional Application No. 61/427,026, filed on Dec. 23, 2010. Theentire teachings of the above applications are incorporated herein byreference.

FIELD OF THE INVENTION

The present invention relates to prodrugs that can be linked to multipledrug molecules.

BACKGROUND OF THE INVENTION

Drug delivery systems are often critical for the safe and effectiveadministration of a biologically active agent. Perhaps the importance ofthese systems is best realized when patient compliance and consistentdosing are taken under consideration. For instance, reducing the dosingrequirement for a drug from four-times-a-day to a single dose per daywould have significant value in terms of ensuring patient compliance andoptimizing therapy. Many of the currently administered prodrugs andformulations require large amounts of drug/excipient/prodrug mixturesfor administration.

Optimization of a drug's bioavailability has many potential benefits.For patient convenience and enhanced compliance it is generallyrecognized that less frequent dosing is desirable. By extending theperiod through which the drug is released, a longer duration of actionper dose is expected. This will then lead to an overall improvement ofdosing parameters such as taking a drug once a day where it haspreviously required four doses per day or dosing once a week or evenless frequently when daily dosing was previously required. Many drugsare presently dosed once per day, but not all of these drugs havepharmacokinetic properties that are suitable for dosing intervals ofexactly twenty-four hours. Extending the period through which thesedrugs are released would also be beneficial.

One of the fundamental considerations in drug therapy involves therelationship between blood levels and therapeutic activity. For mostdrugs, it is of primary importance that serum levels remain between aminimally effective concentration and a potentially toxic level. Inpharmacokinetic terms, the peaks and troughs of a drug's blood levelsideally fit well within the therapeutic window of serum concentrations.For certain therapeutic agents, this window is so narrow that dosageformulation becomes critical.

In an attempt to address the need for improved bioavailability, severaldrug release modulation technologies have been developed. For example,poorly soluble 5,5-diphenylimidazolidine-2,4-diones have beenderivatized into phosphate ester prodrugs to improve solubility (Stellaet al., U.S. Pat. No. 4,260,769, 1981). Enteric coatings have been usedas a protector of pharmaceuticals in the stomach and microencapsulatingactive agents using proteinaceous microspheres, liposomes orpolysaccharides have been effective in abating enzymatic degradation ofthe active agent. Enzyme inhibiting adjuvants have also been used toprevent enzymatic degradation.

A wide range of pharmaceutical formulations provide sustained releasethrough microencapsulation of the active agent in amides of dicarboxylicacids, modified amino acids or thermally condensed amino acids. Slowrelease rendering additives can also be intermixed with a large array ofactive agents in tablet formulations. Many of these formulations,however, deliver relatively low amounts of parent drugs in comparisonwith the overall weight of the formulations.

While microencapsulation and enteric coating technologies impartenhanced stability and time-release properties to active agentsubstances these technologies suffer from several shortcomings.Incorporation of the active agent is often dependent on diffusion intothe microencapsulating matrix, which may not be quantitative and maycomplicate dosage reproducibility. In addition, encapsulated drugs relyon diffusion out of the matrix or degradation of the matrix, or both,which is highly dependent on the chemical properties and watersolubility of the active agent. Conversely, water-soluble microspheresswell by an infinite degree and, unfortunately, may release the activeagent in bursts with limited active agent available for sustainedrelease. Furthermore, in some technologies, control of the degradationprocess required for active agent release is unreliable. For example,because an enterically coated active agent depends on pH to release theactive agent and pH and residence time varies, the release rate isdifficult to control.

Several implantable drug delivery systems have utilized polypeptideattachment to drugs. Additionally, other large polymeric carriersincorporating drugs into their matrices are used as implants for thegradual release of drugs. Yet another technology combines the advantagesof covalent drug attachment with liposome formation where the activeingredient is attached to highly ordered lipid films.

There is a generally recognized need for sustained delivery of drugsthat reduces the daily dosing requirement and allows for controlled andsustained release of the parent drug and also avoids irregularities ofrelease and cumbersome formulations encountered with typical dissolutioncontrolled sustained release methods. Furthermore, there is a need toaccomplish the above listed goals with high relative ratios of parentdrugs in relation to the dry weight of the formulation.

SUMMARY OF THE INVENTION

The present invention accomplishes this by having multiple molecules ofparent drugs attached to carrier moieties and by extending the periodduring which the parent drug is released and absorbed afteradministration to the patient and providing a longer duration of actionper dose than the parent drug itself. In one embodiment, the compoundssuitable for use in the methods of the invention are derivatives ofheteroaryl, lactam-, amide-, imide-, sulfonamide-, carbamate-, urea-,benzamide-, N-acylaniline-, and cyclic amide-, and tertiary aminecontaining parent drugs that are substituted at a nitrogen or oxygenatom with a labile aldehyde-linked prodrug moieties. In one embodiment,the prodrug moieties are hydrophobic and reduce the polarity andsolubility of the parent drug under physiological conditions.

In one embodiment, the invention provides a prodrug compound of FormulaI, IA or IB:

-   -   wherein a is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or        16;    -   e is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,        14, 15 or 16;    -   f is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,        14, 15 or 16, wherein the sum of e and f is at least two;    -   each R₁ and R₂ is independently selected hydrogen, halogen,        —OR₂₀, —SR₂₀, —NR₂₀R₂₁, —C(O)R₂₀, —C(O)OR₂₀, —C(O)NR₂₀R₂₁,        —N(R₂₀)C(O)R₂₁, —CF₃, —CN, —NO₂, —N₃, acyl, optionally        substituted alkoxy, optionally substituted alkylamino,        optionally substituted dialkylamino, optionally substituted        alkylthio, optionally substituted alkylsulfonyl, optionally        substituted aliphatic, optionally substituted aryl and        optionally substituted heterocyclyl;        -   wherein each R₂₀ and R₂₁ is independently selected from            hydrogen, halogen, aliphatic, substituted aliphatic, aryl            and substituted aryl;    -   X₁ is selected from O or S;    -   X₂ is selected from direct bond, O, S or NR₂₀;    -   C1 is a carrier moiety; and    -   each API is independently a biologically active moiety.    -   The invention further relates to prodrugs of secondary amine        containing drugs of Formula LI:

In one embodiment, each API is the same biologically active moiety. Inanother embodiment, the API groups represent two or more differentbiologically active moieties.

The invention further provides a method for sustained delivery of aparent drug by the administration of a conjugate of the parent drug witha labile moiety, wherein the conjugate is represented by Formula I, IAor IB.

DETAILED DESCRIPTION OF THE INVENTION

The present provides a method for attaching multiple parent drugs(biologically active moieties) to a carrier moiety resulting in aconjugate that can undergo spontaneous or enzyme assisted cleavage inphysiological conditions to release the parent drug. In one embodiment,the release of the parent drug is sustained release. The sustainedrelease is accomplished by extending the period during which the parentdrug is released and absorbed after administration to the patient andproviding a longer duration of action per dose than the parent drugitself. In one embodiment, the prodrug moieties are hydrophobic andreduce the polarity and solubility of the parent drug underphysiological conditions.

One of the challenges for delivering a prodrug is the high amount ofprodrug needed to be dosed compared to the parent drug due to the highermolecular weight of the prodrug compared to the parent drug. Having amultivalent carrier moiety that can link two or more parent drugmoieties can decrease the dose load. Also, such a multivalent carriercan link two different APIs. For example, molecules of Aripiprazole andDehydroaripiprazole can be linked to the same carrier moiety. In anotherembodiment, two molecules can be linked to the same carrier so that theywill be released through different mechanisms. For example, a quaternaryammonium prodrug can easily hydrolyze in physiological conditions. Onthe other hand, a parent drug linked through another functional groupthat relies on enzymatic action might release more slowly. Thus, twoparent drugs can be linked to a single carrier moiety, the first via aquaternary ammonium group on one end and the second through a labilefunctional group. This allows one to tailor the release of the twoparent drugs, with faster delivery of one parent drug compared to theother based on chemical reactivity and/or enzymatic activity.

In one embodiment, the invention provides a prodrug compound of FormulaI, IA or IB:

-   -   wherein a is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or        16;    -   e is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,        14, 15 or 16;    -   f is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,        14, 15 or 16, wherein the sum of e and f is at least two;    -   each R₁ and R₂ is independently selected hydrogen, halogen,        —OR₂₀, —SR₂₀, —NR₂₀R₂₁, —C(O)R₂₀, —C(O)OR₂₀, —C(O)NR₂₀R₂₁,        —N(R₂₀)C(O)R₂₁, —CF₃, —CN, —NO₂, —N₃, acyl, optionally        substituted alkoxy, optionally substituted alkylamino,        optionally substituted dialkylamino, optionally substituted        alkylthio, optionally substituted alkylsulfonyl, optionally        substituted aliphatic, optionally substituted aryl and        optionally substituted heterocyclyl;        -   wherein each R₂₀ and R₂₁ is independently selected from            hydrogen, halogen, aliphatic, substituted aliphatic, aryl            and substituted aryl;    -   X₁ is selected from O or S;    -   X₂ is selected from direct bond, O, S or NR₂₀;    -   C1 is a carrier; and    -   each API is independently a biologically active moiety.

The invention further relates to prodrugs of secondary amine containingdrugs of Formula LI:

The invention further provides a method for sustained delivery of aparent drug by the administration of a multivalent conjugate of theparent drug with a labile moiety, wherein the conjugate is representedby Formula I, IA, IB or LI.

In some embodiments, C1 is selected from optionally substitutedaliphatic, aryl or substituted aryl. In some embodiments, C1 is selectedfrom optionally substituted C₁-C₃₀ alkyl, optionally substituted C₂-C₃₀alkenyl, optionally substituted C₁-C₃₀ alkynyl, optionally substitutedC₁-C₃₀ aryl. In some embodiments, C1 is selected from optionallysubstituted bicyclic heteroaryl group selected from benzofuran,benzothiophene, indole, benzimidazole, indazole, benzotriazole,pyrrolo[2,3]pyridine, imidazopyridine, pyrazolopyridine, isoindole,quinoline, isoquinoline, quinazoline, quinoxaline, phthalazine,indazole, purine, indolizine, indole, indoline, isoindoline, benzofuranand chromene. In some embodiments, C1 is a polyethyleneglycol grouphaving a molecular weight of about 400 dalton to about 100,000 dalton.

In some embodiments, C1 is selected from:

whereinc is selected from 0, 1, 2, 3 and 4;g is an integer from 1 to about 1,000;each b and d is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12 and 13;s and t are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,27, 28, 29 and 30;each R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, and R₁₆ is independently selectedfrom absent, hydrogen, halogen, —OR₂₀, —SR₂₀, —NR₂₀R₂₁, —C(O)R₂₀,—C(O)OR₂₀, —C(O)NR₂₀R₂₁, —N(R₂₀)C(O)R₂₁, —CF₃, —CN, —NO₂, —N₃, acyl,optionally substituted alkoxy, optionally substituted alkylamino,optionally substituted dialkylamino, optionally substituted alkylthio,optionally substituted alkylsulfonyl, optionally substituted aliphatic,optionally substituted aryl and optionally substituted heterocyclyl;wherein each R₂₀ and R₂₁ is independently selected from hydrogen,halogen, aliphatic, substituted aliphatic, aryl and substituted aryl;alternatively two R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, and R₁₆ together withthe atoms to which they are attached may form an optionally substituted3, 4, 5, 6 or 7 membered carbocyclic or heterocyclyl ring.

In some embodiments, C1 is a dendrimer.

In some embodiments, the invention relates to a prodrug conjugate ofFormula II:

wherein, each X₁ is independently selected from S or O;each X₂ is selected from absent, O, S or NR₂₀ wherein R₂₀ is selectedfrom hydrogen, halogen, aliphatic, substituted aliphatic, aryl orsubstituted aryl;API-1 is a biologically active moiety; andAPI-2 is a biologically active moiety and is the same or different fromAPI-1.

In some embodiments, the invention relates to a prodrug conjugate havingthe formula:

wherein A₁ and B₁ together with the nitrogen they are attached to form afirst biologically active molecule; and,A₂ and B₂ together with the nitrogen they are attached to form a secondbiologically active molecule.

In some embodiments, the invention relates to a prodrug conjugate havingthe formula:

wherein A₁ and B₁ together with the nitrogen they are attached to form afirst biologically active molecule; and,A₂ and B₂ together with the nitrogen they are attached to form a secondbiologically active molecule.

In some embodiments, the invention relates to a prodrug conjugate havingthe formula:

wherein n is an integer between about 1 and about 50;each R₁₀ and R₁₁ is independently selected from absent, hydrogen,halogen, —OR₂₀, —SR₂₀, —NR₂₀R₂₁, —C(O)R₂₀, —C(O)OR₂₀, —C(O)NR₂₀R₂₁,—N(R₂₀)C(O)R₂₁, —CF₃, —CN, —NO₂, —N₃, acyl, optionally substitutedalkoxy, optionally substituted alkylamino, optionally substituteddialkylamino, optionally substituted alkylthio, optionally substitutedalkylsulfonyl, optionally substituted aliphatic, optionally substitutedaryl or optionally substituted heterocyclyl;wherein each R₂₀ and R₂₁ is selected from hydrogen, halogen, aliphatic,substituted aliphatic, aryl or substituted aryl;alternatively two R₁₀ and R₁₁ together with the atoms to which they areattached may form an optionally substituted 3, 4, 5, 6 or 7 memberedcarbocyclic or heterocyclyl ring.

In some embodiments, the invention relates to a prodrug of a secondaryamine containing parent drug having the formula:

wherein n is an integer between about 1 and about 50;each R₁₀ and R₁₁ is independently selected from absent, hydrogen,halogen, —OR₂₀, —SR₂₀, —NR₂₀R₂₁, —C(O)R₂₀, —C(O)OR₂₀, —C(O)NR₂₀R₂₁,—N(R₂₀)C(O)R₂₁, —CF₃, —CN, —NO₂, —N₃, acyl, optionally substitutedalkoxy, optionally substituted alkylamino, optionally substituteddialkylamino, optionally substituted alkylthio, optionally substitutedalkylsulfonyl, optionally substituted aliphatic, optionally substitutedaryl or optionally substituted heterocyclyl;wherein each R₂₀ and R₂₁ is selected from hydrogen, halogen, aliphatic,substituted aliphatic, aryl or substituted aryl;alternatively two R₁₀ and R₁₁ together with the atoms to which they areattached may form an optionally substituted 3, 4, 5, 6 or 7 memberedcarbocyclic or heterocyclyl ring.

In a preferred embodiment, n is an integer between about 4 and about 26.

In some embodiments, the invention relates to a prodrug conjugate withthree drug moieties attached to a carrier group. For example, threeparent drug moieties can be attached to an aconitic acid based carrier:

Other tricarboxylic acid compounds such as citric acid, isocitric acid,and trimesic acid can be used as carriers. In one embodiment, theinvention relates to prodrugs having the formula:

API-1 and API-2 are as defined above, and API-3 is a biologically activemoiety and is the same or different from API-1, and API-2.

Prodrugs of Lac Tam, Cyclic Urea, Imide and Carbamate ContainingPharmacophores

In one embodiment, the compounds of the invention are derivatives oflactam-, imide-, carbamate-, and cyclic urea-, -containing parent drugsthat are substituted at the amide nitrogen or oxygen atom with labilealdehyde-linked prodrug moieties.

In some embodiments, the invention relates to a prodrug conjugate havingthe formula:

wherein h is 3 or 4;

wherein each R₁₀₀, R₁₀₁, R₁₀₂, and R₁₀₃ is independently selected fromabsent, hydrogen, halogen, —OR₁₀, —SR₁₀, —NR₁₀R₁₁—, optionallysubstituted aliphatic, optionally substituted aryl or optionallysubstituted heterocyclyl; alternatively, two R₁₀₀, and R₁₀₁ togetherform an optionally substituted carbocyclic or heterocyclyl ring;C1 is as previously defined; and,

X₁₀₀ is —CH— or —N—.

In some embodiments, the invention relates to a prodrug conjugateshaving the formula:

wherein D together with oxygen to which it is attached forms abiologically active moiety; and, D₂ together with oxygen to which it isattached forms a biologically active moiety; and C1 is as previouslydefined.

In some embodiments, the invention relates to a prodrug conjugate havingthe formula:

wherein n is selected from 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30.

In one embodiment, the parent drug moieties (APIs) are selected fromTable 1. In one embodiment, the prodrug is a compound of Formula IIwherein API-1 and API-2 are selected from Table-1. In one embodimentboth API-1 and API-2 represent the same parent drug.

TABLE 1

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9

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11

12

In one embodiment, the parent drug moieties (APIs), are selected fromTable 2. In one embodiment, the prodrug is a compound of Formula IIwherein API-1 and API-2 are selected from Table-2. In one embodimentboth API-1 and API-2 represent the same parent drug.

TABLE 2

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54

In one embodiment, the parent drug moieties (APIs) are selected fromTable 3. In one embodiment, the prodrug is a compound of Formula IIwherein API-1 and API-2 are selected from Table 3. In one embodimentboth API-1 and API-2 represent the same parent drug.

TABLE 3

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Prodrugs of Acylanilines

In one embodiment, the compounds suitable for use in the methods of theinvention are derivatives of acylaniline-, -containing parent drugs thatare substituted at the amide nitrogen or oxygen atom with labilealdehyde-linked prodrug moieties.

In one embodiment, compounds of the present invention are represented byFormula III below, or its geometric isomers, enantiomers, diastereomers,racemates, pharmaceutically acceptable salts and solvates thereof:

wherein each R₅₀, R₅₁, R₅₂, R₅₃, R₅₄ and R₅₅ is independently selectedfrom hydrogen, halogen, —OR₁₀, —SR₁₀, —NR₁₀R₁₁—, optionally substitutedaliphatic, optionally substituted aryl or optionally substitutedheterocyclyl; alternatively, two or more R₅₀, R₅₁, R₅₂, R₅₃, R₅₄ and R₅₅together form an optionally substituted ring.

In one embodiment, the parent drug moieties (APIs), are selected fromTable 4. In one embodiment, the prodrug is a compound of Formula IIwherein API-1 and API-2 are independently selected from Table-4. In oneembodiment both API-1 and API-2 represent the same parent drug.

TABLE 4

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78

Thiazolidinones

In one embodiment, the compounds suitable for use in the methods of theinvention are derivatives of thioazolidine-, -containing parent drugsthat are substituted at an amide nitrogen or oxygen atom with labilealdehyde-linked prodrug moieties.

In one embodiment, compounds of the present invention are represented byFormula IV below, or its geometric isomers, enantiomers, diastereomers,racemates, pharmaceutically acceptable salts and solvates thereof:

wherein Cy₂ is an optionally substituted heterocyclic ring; and X₅ isselected from absent, —S—, —O—, —S(O)—, —S(O)₂—, —N(R₁₀)—, —C(O)—,—C(OR₁₀)(R₁₁)—, —[C(R₁₀)(R₁₁)]_(v)—, —O[C(R₁₀)(R₁₁)]_(v)—,—O[C(R₁₀)(R₁₁)]_(v)O—, —S[C(R₁₀)(R₁₁)]_(v)O—, —NR₁₂[C(R₁₀)(R₁₁)]_(v)O—,—NR₁₂[C(R₁₀)(R₁₁)]_(v)S—, —S[C(R₁₀)(R₁₁)]_(v)—, —C(O)[C(R₁₀)(R₁₁)]_(v)—,and —C(R₁₀)(R₁₁)═C(R₁₀)(R₁₁)—; wherein v is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9or 10.

In one embodiment, the parent drug moieties (APIs), are independentlyselected from Table 5. In one embodiment, the prodrug is a compound ofFormula II wherein API-1 and API-2 are selected from Table-5. In oneembodiment both API-1 and API-2 represent the same parent drug.

TABLE 5

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Barbiturates

In one embodiment, the compounds suitable for use in the methods of theinvention are derivatives of barbiturates that are substituted at anamide nitrogen or oxygen atom with labile aldehyde-linked prodrugmoieties.

In one embodiment, the parent drug moieties (APIs), are selected fromTable 6. In one embodiment, the prodrug is a compound of Formula IIwherein API-1 and API-2 are selected from Table-6. In one embodimentboth API-1 and API-2 represent the same parent drug.

TABLE 6

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16wherein M is a pharmaceutically acceptable cation.

Prodrugs of Pyridone and Pyrimidine Containing Parent Drugs

In one embodiment, the compounds suitable for use in the methods of theinvention are derivatives of pyridine and pyrimidine containing parentdrugs that are substituted at the amide nitrogen or oxygen atom withlabile aldehyde-linked prodrug moieties.

In one embodiment, the parent drug moieties (APIs), are selected fromTable 7. In one embodiment, the prodrug is a compound of Formula IIwherein API-1 and API-2 are selected from Table-7. In one embodimentboth API-1 and API-2 represent the same parent drug.

TABLE 7

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Prodrugs of Benzamide Parent Drugs

In one embodiment, the compounds suitable for use in the methods of theinvention are derivatives of benzamide containing parent drugs that aresubstituted at the amide nitrogen or oxygen atom with labilealdehyde-linked prodrug moieties.

In one embodiment, the parent drug moieties (APIs) are independentlyselected from Table 8. In one embodiment, the prodrug is a compound ofFormula II wherein API-1 and API-2 are selected from Table-8. In oneembodiment both API-1 and API-2 represent the same parent drug.

TABLE 8

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Prodrugs of Imide Containing Parent Drugs

In one embodiment, the compounds suitable for use in the methods of theinvention are derivatives of imide containing parent drugs that aresubstituted at the amide nitrogen or oxygen atom with labilealdehyde-linked prodrug moieties.

In one embodiment, the parent drug moieties (APIs) are independentlyselected from Table 9. In one embodiment, the prodrug is a compound ofFormula II wherein API-1 and API-2 are selected from Table-9. In oneembodiment both API-1 and API-2 represent the same parent drug.

TABLE 9

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Prodrugs of Cyclic Ureas

In one embodiment, the compounds suitable for use in the methods of theinvention are derivatives of cyclic urea-containing parent drugs thatare substituted at either of the urea nitrogens or oxygen with labilealdehyde-linked prodrug moieties.

In one embodiment, the parent drug moieties (APIs), are independentlyselected from Table 10. In one embodiment, the prodrug is a compound ofFormula II wherein API-1 and API-2 are selected from Table-10. In oneembodiment both API-1 and API-2 represent the same parent drug.

TABLE 10 No Structure  1

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Prodrugs of Sulfonamide Parent Drugs

In one embodiment, the compounds suitable for use in the methods of theinvention are derivatives of sulfonamide parent drugs that aresubstituted at the sulfonamide nitrogen or oxygen atom with labilealdehyde-linked prodrug moieties.

wherein A and B together with the sulfonamide group forms the parentdrug; and, A2 and B2 together with the sulfonamide group form the parentdrug.

In one embodiment, the parent drug moieties (APIs), are selected fromTable 11. In one embodiment, the prodrug is a compound of Formula IIwherein API-1 and API-2 are independently selected from Table-11. In oneembodiment both API-1 and API-2 represent the same parent drug.

TABLE 11

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Prodrugs of Tertiary Amine Containing Parent Drugs

In some embodiments, the invention relates to a prodrug conjugateshaving the Formula V:

wherein A₁, B₁ and E₁ together with the nitrogen they are attached toform a tertiary amine containing first biologically active molecule;A₂, B₂ and E₂ together with the nitrogen they are attached to form atertiary amine containing second biologically active molecule;X₁ is selected from O or S;X₂ is selected from direct bond, O, S or NR₂₀ wherein R₂₀ is selectedfrom hydrogen, halogen, aliphatic, substituted aliphatic, aryl orsubstituted aryl;X— is a pharmaceutically acceptable counterion; and,C1 represents a carrier moiety.

In some embodiments, the invention relates to a prodrug conjugateshaving the Formula VI:

wherein n is an integer between 1 and 50;n, A₁, E₁, B₁, A₂, E₂, B₂, X₁, X₂, R₁₀, R₁₁ and X— are as defined above.

In some embodiments, n is selected from 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and30.

In some embodiments, the invention relates to a prodrug conjugateshaving the Formula VII:

n, A₁, B₁, A₂, E₂, B₂, X₁, X₂, and X— are as defined above.

The tertiary amine-containing parent drug may be any tertiaryamine-containing drug that induces a desired local or systemic effect.Such drugs include broad classes of compounds. In general, thisincludes: analgesic agents; anesthetic agents; antiarthritic agents;respiratory drugs, including antiasthmatic agents; anticancer agents,including antineoplastic agents; anticholinergics; anticonvulsants;antidepressants; antidiabetic agents; antidiarrheals; antihelminthics;antihistamines; antihyperlipidemic agents; antihypertensive agents;anti-infective agents such as antibiotics and antiviral agents;antiinflammatory agents; antimigraine preparations; antinauseants;antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics;antispasmodics; antitubercular agents; antiulcer agents; antiviralagents; anxiolytics; appetite suppressants; attention deficit disorder(ADD) and attention deficit hyperactivity disorder (ADHD) drugs;cardiovascular preparations including calcium channel blockers, CNSagents; beta-blockers and antiarrhythmic agents; central nervous systemstimulants; cough and cold preparations, including decongestants;diuretics; genetic materials; gastrointestinal (GI) motility agents;herbal remedies; hormones; hormonolytics; hypnotics; hypoglycemicagents; immunosuppressive agents; leukotriene inhibitors; mitoticinhibitors; muscle relaxants; narcotic antagonists; nicotine;nutritional agents, such as vitamins, essential amino acids and fattyacids; ophthalmic drugs such as antiglaucoma agents; parasympatholytics;peptide drugs; psychostimulants; sedatives; steroids; sympathomimetics;tranquilizers; and vasodilators including general coronary, peripheraland cerebral.

Examples of tertiary amine-containing antibiotic parent drugs from whichthe prodrugs of the invention may be derived include: clindamycin,ofloxacin/levofloxacin, pefloxacin, quinupristine, rolitetracycline, andcefotiam.

Examples of tertiary amine-containing antifungal parent drugs from whichthe prodrugs of the invention may be derived include: butenafine,naftifine, and terbinafine.

Examples of tertiary amine-containing antimalarials and antiprotozoalsparent drugs from which the prodrugs of the invention may be derivedinclude: amodiaquine, quinacrine, sitamaquine, quinine.

Examples of tertiary amine-containing HIV protease inhibitor parentdrugs from which the prodrugs of the invention may be derived include:saquinavir, indinavir, atazanavir and nelfinavir. Anti-HIV drugs alsoinclude maraviroc and aplaviroc for inhibition of HIV entry.

Examples of tertiary amine-containing anticonvulsants/antispasmodicsparent drugs from which the prodrugs of the invention may be derivedinclude: atropine, darifenancin; dicyclomine; hyoscayamine, tiagabine,flavoxate; and alverine.

Examples of tertiary-amine containing antidepressant parent drugs fromwhich the prodrugs of the invention are derived include: amitriptyline,adinazolam, citalopram, cotinine, clomipramine, doxepin, escitalopram,femoxetine, imipramine, minaprine, moclobemide, mianserin, mirtazapine,nefazodone, nefopam, pipofenazine, promazine, ritanserin, trazodone,trimipramine and venlafaxine.

Examples of tertiary amine-containing antiemetic parent drugs from whichthe prodrugs of the invention are derived include: aprepitant,buclizine, cilansetron, cyclizine, dolasetron, granisetron, meclizine,ondansetron, palonosetron, ramosetron, thiethylperazine,trimethobenzamide, scopolamine, and prochlorperazine.

Examples of tertiary amine-containing antihistamine parent drugs fromwhich the prodrugs of the invention are derived include:acetprometazine, azatadine, azelastine, brompheniramine, carbinoxamine,chlorpheniramine, clemastine, dexobrompheniramine, diphenhydramine,diphenylpyraline, doxepin, emadastine, loratadine, mequitazine,olopatadine, phenindamine, pheniramine, promethazine, tripelennamine,triprolidine, astemizole, cetirizine, fexofenadine, terfenadine,latrepirdine, ketotifen, cyproheptadine, hydroxyzine, clobenzepamdoxylamine, cinnarizine, orphenadrine.

Examples of tertiary amine-containing antiparkinsonian parent drugs fromwhich prodrugs of the invention are derived include: cabergoline,ethopropazine, pergolide, selegiline, metixene, biperiden, cycrimine,procycladine and apomorphine.

Examples of tertiary amine-containing antipsychotic parent drugs fromwhich prodrugs of the invention are derived include: acetophenazine,amisulpride, aripiprazole, bifeprunox, blonanserin, cariprazine,carphenazine, clopenthixol, clozapine, dehydro aripiprazole,someperidone, droperidol, flupenthixol, fluphenazine, fluspirilene,haloperidol, iloperidone, lurasidone, mesoridazine, molindole,nemanopride, olanzapine, perospirone, perphenazine, PF-00217830(Pfizer), pipotiazine, propericiazine, quetiapine, remoxipride,risperidone, sertindole, SLV-313 (Solvay/Wyeth), sulpiride,thioproperazine, thioridazine, thiothixene, trifluoperazine,ziprasidone, zotepine, pimozide, benzquinamide, triflupromazine,tetrabenazine, melperon, asenapine, chlorprothixene, spiperone andchlorpromazine.

Examples of tertiary amine-containing anxiolytic parent drugs from whichprodrugs of the invention are derived include: buspirone, and loxapine.

Examples of tertiary amine-containing nootroopic (memory and cognitiveenhancers) parent drugs from which prodrugs of the invention are derivedinclude: donepezil, galantamine, latrepirdine, nicotine, TC-5616(Targacept, Inc.) having the IUPAC name:N-[(2S,3S)-2-(pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide.

Examples of tertiary amine-containing parent drugs for erectiledysfunction from which prodrugs of the invention are derived include:apomorphine and sildenafil.

Examples of tertiary amine-containing parent drugs for migraine headachefrom which prodrugs of the invention are derived include: almotriptan,naratriptan, rizatriptan, sumatriptan, zolmitriptan, dihydroergotamine,ergotamine, eletripan and lisuride.

Examples of tertiary amine-containing parent drugs for the treatment ofalcoholism from which prodrugs of the invention are derived include:naloxone and naltrexone. Other narcotic antagonist amine containingparent drugs for treatment of substance abuse from which prodrugs of theinvention are derived include: levallorphan, nalbuphine, nalorphine andnalmefene.

Examples of a tertiary amine-containing parent drug for the treatment ofaddiction from which a prodrug of the invention is derived include:buprenorphine, isomethadone, levomethadyl acetate, methadyl acetate,nor-acetyl levomethadol, and normethadone.

Examples of tertiary amine-containing muscle relaxant parent drugs fromwhich prodrugs are derived include: cyclobenzaprine, nefopam,tolperisone, orphenadrine, and quinine.

Examples of tertiary amine-containing nonsteroidal anti-inflammatoryparent drugs from which prodrugs of the invention are derived include:etodolac, meloxicam, ketorolac, lornoxicam and tenoxicam. Examples oftertiary amine-containing opioid parent drugs from which prodrugs of theinvention are derived include alfentanil, anileridine, buprenorphine,butorphanol, clonitazene, codeine, dihydrocodeine, dihydromorphin,fentanyl, hydromorphone, meperidine, metazocine, methadone, morphine,oxycodone, hyrdocodone, oxymorphone, pentazocine, remifentanil, andsufentanil.

Examples of other tertiary amine-containing analgesic parent drugs fromwhich prodrugs of the invention are derived include: methotrimeprazine,tramadol, nefopam, phenazocine, propiram, quinupramine, thebaine andpropoxyphene.

Examples of tertiary amine-containing sedatives/hypnotics from which theprodrugs of the invention may be derived include: eszopiclone,flurazepam, propiomazine, and zopiclone.

Examples of tertiary amine-containing local analgesic parent drugs fromwhich prodrugs of the invention are derived include: bupivacaine,dexmedetomidine, dibucaine, dyclonine, lodicaine, mepivacaine, procaine,and tapentadol and ropivacaine.

Examples of tertiary amine-containing antianginals from which theprodrugs of the invention may be derived include: ranozaline, bepridil.

Examples of tertiary amine-containing antiarrhythmics from which theprodrugs of the invention may be derived include: amiodarone, aprindine,encainide, moricizine, procainamide, diltiazem, verapamil, bepridil.

Examples of tertiary amine-containing antihypertensives from which theprodrugs of the invention may be derived include: azelnidipine,deserpidine, ketanserin, reserpine, and sildenafil.

Examples of tertiary amine-containing antithrombotics from which theprodrugs of the invention may be derived include: clopidogrel andticlopidine.

Examples of tertiary amine-containing antineoplastic parent drugs fromwhich prodrugs of the invention are derived include: dasatinib,flavopiridol, gefitinib, imatinib, sunitinib, topotecan, vinblastine,vincristine, fincesine, vinorelbine, vinorelbine, tamoxifen, tremifene,and tesmilifene.

Examples of tertiary amine-containing drugs parent drugs for use intreating irritable bowel syndrome (IBS) from which the prodrugs of theinvention are derived include asimadoline.

Examples of other tertiary amine-containing parent drugs from which theprodrugs of the invention are derived include: antimuscarinics andanticholinergics such as benzotropine, procyclidine andtrihexylphanidyl; alpha andrenergic blockers such as dapiprazole,dexmedetomidine and nicergoline; anorexics such as diethylpropian,benzapehtamine, phendimetrazine, and sibutramine; antidiarrhels such asdiphenoxylate and loperamide, antikinetic and antihypertensives such asclonidine; antiosteoporotics such as raloxifene; antipruritics such asmethyldilazine; antitussives such as dextromethorphan; antiulcerativessuch as pirenzepine; cholinesterase inhibitors such as galantamine;gastroprokinetics such as alvimopan, cisapride, and piboserod; miglustatfor treating glycosphingolipid lysosomal storage disorder; clomifene asgonad stimulating prinicipal; neuromuscular blockers such asdihydro-beta-erythrodoidine, niotropics such as rivastigmine, oxytocicssuch as methylergonovine; antiametics such as chloroquine; respiratorystimulants such as doxapram; muscarinic receptor antagonists fortreating urinary incontinence such as oxybutynin and solifenacin;calcium channel blockers such as flunarizine; anthelmintics such asdiethylcarbamazine and quinacrine; miotics such as physostigmine;neuroprotectives such as lubeluzole; immunosuppressants such asmycophenolate mofetil; and stimulants such as nicotine.

Preferred tertiary amine-containing parent drugs from which prodrugs ofthe invention are derived include: amisulpride, aripiprazole, asenapine,cariprazine, citalopram, dehydroaripiprazole, escitalopram, galantamine,iloperidone, latrepirdine, olanzapine, paliperidone, perospirone,risperidone, and ziprasidone.

The present invention is intended to encompass any parent drug compoundor any substituted parent drug compound which contains a tertiary aminegroup and which is biologically active and can be derivatized accordingto the present invention to afford the corresponding prodrugs. While thetertiary amine-containing parent drugs from which the prodrugs of theinvention may be derived are numerous, many of the chemical structuresof the prodrugs of the invention can be characterized by certain generalstructure types. One type includes those wherein the tertiary aminenitrogen is part of a cyclic (including bicyclic or tricyclic) aliphaticgroup such as piperidine, piperazine, morpholine, pyrrolidine, azapine,and diazapine. Another type includes those wherein the tertiary aminenitrogen is part of an alkyl amine group such as a diethyl and/ordimethyl amine.

In some embodiments, the invention relates to a prodrug conjugateshaving the Formula VIII:

wherein A— is a pharmaceutically acceptable counterion; and X₁, and X₂,are as defined above.

In one embodiment, the parent drug moieties (APIs) are independentlyselected from Table 12. In one embodiment, the prodrug is a compound ofFormula II wherein API-1 and API-2 are selected from Table-12. In oneembodiment both API-1 and API-2 represent the same parent drug.

TABLE 12

Prodrugs of Heteroaryl Parent Drugs

In one embodiment, the compounds suitable for use in the methods of theinvention are derivatives of heteroaryl NH-containing parent drugs thatare substituted at the NH nitrogen atom with labile prodrug moieties.Preferably, the prodrug moieties are hydrophobic and reduce thesolubility at physiological pH (pH 7.0), as well as modulate polarityand lipophilicity parameters of the prodrug as compared to the parentdrug.

In one embodiment, the invention provides a prodrug compound of FormulaIX:

or a pharmaceutically acceptable salt thereof, wherein each of X₁₀ toX₁₇ is independently N or CR, provided that at least one of X₁₀-X₁₇ isCR. The R groups combine to form the portion of the prodrug compound inaddition to the five-membered heteroaromatic ring. For example, the Rgroups can be independently hydrogen, optionally substituted aliphatic,aromatic, heteroaromatic or a combination thereof. The R groups can alsobe taken together with the carbon atoms to which they are attached toform one or more optionally substituted fused ring systems.

In a preferred embodiment, the invention relates to a prodrug conjugateof Formula X:

wherein, n, X₁₀-X₁₇, X₁, X₂, R₁₀, and R₁₁ are as defined above.

Heteroaromatic NH-containing parent drugs include broad classes ofcompounds. In general, this includes: analgesic agents; anestheticagents; antiarthritic agents; respiratory drugs, including antiasthmaticagents; anticancer agents, including antineoplastic agents;anticholinergics; anticonvulsants; antidepressants; antidiabetic agents;antidiarrheals; antihelminthics; antihistamines; antihyperlipidemicagents; antihypertensive agents; anti-infective agents such asantibiotics and antiviral agents; antiinflammatory agents; antimigrainepreparations; antinauseants; antiparkinsonism drugs; antipruritics;antipsychotics; antipyretics; antispasmodics; antitubercular agents;antiulcer agents; antiviral agents; anxiolytics; appetite suppressants;attention deficit disorder (ADD) and attention deficit hyperactivitydisorder (ADHD) drugs; cardiovascular preparations including calciumchannel blockers, CNS agents; beta-blockers and antiarrhythmic agents;central nervous system stimulants; nootropics; cough and coldpreparations, including decongestants; diuretics; genetic materials;herbal remedies; hormonolytics; hypnotics; hypoglycemic agents;immunosuppressive agents; leukotriene inhibitors; mitotic inhibitors;muscle relaxants; narcotic antagonists; opioid agonists; nicotine;nutritional agents, such as vitamins, essential amino acids and fattyacids; ophthalmic drugs such as antiglaucoma agents; parasympatholytics;peptide drugs; psychostimulants; sedatives; steroids; sympathomimetics;tranquilizers; and vasodilators including general coronary, peripheraland cerebral.

Specific heteroaromatic NH-containing parent drugs represent a varietyof drug classes. Such drugs include tranquilizers and sedatives, such asmepiprazole and dexmedetomidine; anthelmintic agents, such asalbendazole, carbendazole, cyclobendazole, mebendazole andthiabendazole; antimigraine agents, such as almotriptan, dolasetron,eletriptan, lisuride, naratriptan, rizatriptan, sumatriptan,frovatriptan, zolmitriptan and ergotamine; treatments for irritablebowel syndrome, such as alosetron; antiviral agents, such as delavirdineand atevirdine; antihypertensive agents, such as bopindolol, bucindolol,candesartan, deserpidine, mibefradil, ergoloid mesylate, indoramin,irbesartan, mepindolol, olmesartan, reserpine, rescinnamine, losartan,tasosartan, valsartan, raubasine, syrosingopine, carmoxirole andrescimetol; anti-Parkinson agents, such as cabergoline, pergolide,bromocriptine and terguride; bronchodilators, such as ambuphylline;antiulcerative agents, such as cimetidine, lansoprazole, omeprazole,pantaprozole and rabeprazole; antibacterial agents, such as cefatrizineand daptomycin; oxytocic agents, such as ergonovine andmethylergonovine; analgesics, such as etodolac; antineoplastic agents,such as liarozole, pemetrexed, thiamiprine, vinblastine, vincristine,vindesine, vinorelbine, voacamine and venflunine; antidepressants, suchas oxypertine, indalpine and roxindole; anti-allergic agents, such aspemirolast, tazanolast and traxanox; cardiotonic agents, such aspimobendan and sulmazole; antiasthmatics, such as pranlukast;antiemetics, such as ramosetron, tropisetron and alizapride;vasodilators, such as bendazole and tadalafil; anti-gout agents, such asallopurinol; antirheumatic agents, such as azathioprine; mydriatics,such as yohimbine; therapies for congestive heart failure, such asconivaptan; and hormonal agents, such as adrenoglomerulotropin,octreotide, somatostatin, exenatide, teriparatide, leuprorelin andgoserelin.

In one embodiment, the parent drug is a peptide comprising at least oneheteroaromatic NH group. Such peptides include peptides comprising from2 to about 50, from 2 to about 40, from 2 to about 20 or from 2 to about12 amino acid residues, including at least one residue selected fromtryptophan and histidine. Suitable peptides include, but are not limitedto, thyrotropin releasing hormone (TRH), exenatide, daptomycin,octreotide, somatostatin, teriparatide, leuprorelin and goserelin.

While the heteroaromatic NH-containing parent drugs from which theprodrugs of the invention may be derived are numerous, many of thechemical structures of the prodrugs of the invention can becharacterized by certain general structure types. One type includescompounds wherein the heteroaromatic group is a pyrrole group. Anothertype includes compounds wherein the heteroaromatic group is an imidazolegroup. Another type includes compounds wherein the heteroaromatic groupis a 1,2,3- or 1,2,4-triazole group. Another type includes compoundswherein the heteroaromatic group is a tetrazole group. Another typeincludes compounds wherein the heteroaromatic group is a benzimidazolegroup. Another type includes compounds wherein the heteroaromatic groupis an indole group. Another type includes compounds wherein theheteroaromatic group is a pyrazole group.

Benzimidazole-containing parent drugs which can be modified to produceprodrugs of the invention include albenazole, carbendazole,cyclobendazole, lansoprazole, liarozole, mebendazole, mizolastine,omeprazole, pantaprazole, pimobendan, rabeprazole, thiabendazole,bendazol and mibepradil. Preferred benzimidazole-containing drugsinclude lansoprazole, mibefradil and pimobendan.

Imidazole-containing parent drugs which can be modified to produceprodrugs of the invention include alosetron, ambuphylline, cimetidine,conivaptan, dexmedetomidine, ramosetron, thiamiprine, sulmazole,azathioprine, exenatide, teriparatide, thyrotropin releasing hormone(TRH), goserelin and leuprorelin. Preferred imidazole-containing drugsinclude conivaptan, sulmazole and azathioprine.

Indole-containing parent drugs which can be modified to produce prodrugsof the invention include almotriptan, atevirdine, bopindolol,bromocriptine, bucindolol, cabergoline, delavirdine, deserpidine,dolasetron, eletriptan, ergoloid mesylate, ergonovine, etodolac,frovatriptan, indoramin, lisuride, mepidolol, methylergonovine,naratriptan, oxypertine, pemetrexed, pergolide, rescinnamine, reserpine,rizatriptan, sumatriptan, tadalafil, tropisetron,adrenoglomerulotriptan, bromocriptine, ergotamine, indalpine, raubasine,reserpiline, roxindole, syrosingopine, terguride, vinblastine,vincristine, vindesine, vinorelbine, voacamine, vinflunineatevirdine,carmoxirole, rescimetol, yohimbine, zolmitriptan, octreotide,somatostatin, exenatide, teriparatide, daptomycin, leuprorelin andgoserelin. Preferred indole-containing drugs include bopindolol,bucindolol, cabergoline, dolasetron, indoramin, oxypertine, pergolide,rescinnamine, reserpine, atevirdine, carmoxirole and rescimetol.

Pyrazole-containing parent drugs which can be modified to produceprodrugs of the invention include mepiprazole and allopurinlol.

Tetrazole-containing parent drugs which can be modified to produceprodrugs of the invention include candesartan, irbesartan, losartan,olmesartan, pemirolast, pranlukast, tasosartan, traxanox and valsartan.

Triazole-containing parent drugs which can be modified to produceprodrugs of the invention include cefatrizine and alizapride.

Particularly preferred parent drugs which can be modified according tothe invention include bopindolol, bucindolol, cabergoline, candesartan,cefatrizine, conivaptan, indoramin, irbesartan, lansoprazole,mibefradil, olmesartan, oxypertine, pemirolast, pergolide, pimobendan,rescinnamine, reserpine, valsartan, sulmazole, azathioprine, atevirdine,carmoxirole and rescimetol.

In one embodiment, the parent drug moieties (APIs) are selected fromTable 13. In one embodiment, the prodrug is a compound of Formula IIwherein API-1 and API-2 are selected from Table 13. In one embodimentboth API-1 and API-2 represent the same parent drug.

TABLE 13

In another aspect of the invention a general method to synthesizeprodrugs that can be linked to multiple drug molecules is provided(Scheme 1).

wherein each LG-1 and LG-2 is independently a leaving group, preferablya chloride, bromide or iodide.

In another aspect of the invention a general method to synthesizeprodrugs that can be linked to two parent drug molecules through alkylgroup is provided (Scheme 2). The same methodology can be used tosynthesize prodrugs with branched and substituted alkyl groups.

wherein n is an integer between about 1 and about 50, preferably betweenabout 4 and about 26.

In one embodiment, the dicarboxylic acid from Scheme 2 is selected fromoxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid,pimelic acid, suberic acid, azelaic acid, sebacic acid, undecanedioicacid, dodecanedioic acid, ortho-, para- or meta-phthalic acid, maleicacid, fumaric acid, glutaconic acid, traumatic acid or muconic acid. Inone embodiment, the dicarboxylic acid is reacted with one moleequivalent or less of thionyl chloride to give a mixture of mono anddisubstituted acid chloride. In another embodiment, the dicarobxylicacid is reacted with two or more mole equivalents of thionyl chloride.The acid chlorides can be converted to chloromethyl esters by reactingwith trioxane or paraformaldehyde using zirconium tetrachloride as theLewis acid. (Mudryk, B. et. al., Tetrahedron Letters 43(36), 2002,6317-6318). The chloromethyl esters can be reacted with reactive APIs,such as amine containing pharmacophores to give the final conjugates.Methods for attaching biologically active agents containing amine groupsthrough labile groups are disclosed in U.S. application Ser. No.12/823,102. The methods described therein can be adapted to convertdicarboxylic acid containing carrier groups herein.

In another aspect of the invention a general method to synthesizeprodrugs of aripiprazole that can be linked to two aripiprazolemolecules through alkyl group is provided (Scheme 3). The inventionfurther provides a prodrug of aripiprazole selected from Table 14.

TABLE A Compound No. Structure  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

In one embodiment, the compounds of Formula I, IA or IB are lesssoluble, and are preferably at least an order of magnitude less soluble,as compared to the parent drug from which they were derived. In oneembodiment, the prodrugs of Formula I, IA or IB have an aqueoussolubility of less than about 0.5 mg/ml, preferably less than about 0.1mg/mL, preferably less than about 0.01 mg/mL, preferably less than about0.001 mg/mL, preferably less than about 0.0001 mg/mL and even morepreferably less than about 0.00001 mg/ml when solubility is measured ina phosphate buffer (pH 7.4) at room temperature.

In a preferred embodiment, a compound of the invention providessustained delivery of the parent drug over hours, days, weeks or monthswhen administered, for example, orally or parenterally, to a subject.For example, the compounds can provide sustained delivery of the parentdrug for at least 8, 12, 24, 36 or 48 hours or at least 4, 7, 15, 30,60, 75 or 90 days or longer. Without being bound by a theory, it isbelieved that the compounds of the invention form an insoluble depotupon parenteral administration, for example subcutaneous, intramuscularor intraperitoneal injection. In one embodiment a prodrug of theinvention may further comprise a sustained release delivery system forproviding additional protection of the prodrug from enzymatic orchemical degradation.

In another embodiment, the invention provides a method for sustaineddelivery of a parent lactam, amide, imide, sulfonamide, carbamate, urea,benzamide, or acylaniline containing drug to a subject in need thereof.Each of these groups comprises an amidic N—H group. The method comprisesadministering to the subject an effective amount of a prodrug formed bysubstituting on the NH group a labile, hydrophobic aldehyde-linkedprodrug moiety wherein the prodrug has reduced solubility underphysiological conditions compared to the parent drug and provides forlonger sustained therapeutic levels of the parent drug followingadministration than observed levels following administration of theparent drug. In a preferred embodiment, the amidic N—H group has a pKaof about 5 to about 22, preferably about 5 to about 21, and preferablyabout 5 to about 20.

Prodrugs of Secondary Amine Drugs

The invention further relates to prodrugs of secondary amine containingdrugs of Formula LI:

In some embodiments, the invention relates to a prodrug conjugate havingthe formula:

wherein A₁ and B₁ together with the nitrogen they are attached to form afirst biologically active molecule; and,A₂ and B₂ together with the nitrogen they are attached to form a secondbiologically active molecule.

In some embodiments, the invention relates to a prodrug of a secondaryamine containing parent drug having the Formula LI-A:

wherein n is an integer between about 1 and about 50;

X₁ is S or O;

X₂ is selected from direct bond, O, S or NR₂₀;each R₁₀ and R₁₁ is independently selected from absent, hydrogen,halogen, —OR₂₀, —SR₂₀, —NR₂₀R₂₁, —C(O)R₂₀, —C(O)OR₂₀, —C(O)NR₂₀R₂₁,—N(R₂₀)C(O)R₂₁, —CF₃, —CN, —NO₂, —N₃, acyl, optionally substitutedalkoxy, optionally substituted alkylamino, optionally substituteddialkylamino, optionally substituted alkylthio, optionally substitutedalkylsulfonyl, optionally substituted aliphatic, optionally substitutedaryl or optionally substituted heterocyclyl; wherein each R₂₀ and R₂₁ isselected from hydrogen, halogen, aliphatic, substituted aliphatic, arylor substituted aryl;alternatively two R₁₀ and R₁₁ together with the atoms to which they areattached may form an optionally substituted 3, 4, 5, 6 or 7 memberedcarbocyclic or heterocyclyl ring.

In a preferred embodiment, n is selected from 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29and 30.

The secondary amine-containing parent drugs (designated in Formula LI asAPI-1 and API-2) can be any secondary amine-containing parent drug thatinduces a desired local or systemic effect. Such parent drugs includebroad classes of compounds. Several examples include: respiratory drugs,including antiasthmatic agents; analgesic agents; antidepressants;antianginal agents; antiarrhythmic agents; antihypertensive agents;antidiabetic agents; antihistamines; anti-infective agents such asantibiotics; antiinflammatory agents; antiparkinsonism drugs;antipsychotics; antipyretic agents; antiulcer agents; attention deficithyperactivity disorder (ADHD) drugs; central nervous system stimulants;cough and cold preparations, including decongestants; andpsychostimulants.

Examples of secondary-amine containing parent drugs from which prodrugsof the invention may be derived include: alprenolol, acebutolol,amidephrine, amineptine, amosulalol, amoxapine, amphetaminil, atenolol,atomoxetine, balofloxacin, bamethan, befunolol, benazepril, benfluorex,benzoctamine, betahistine, betaxolol, bevantolol, bifemelane,bisoprolol, brinzolamide, bufeniode, butethamine, camylofine, carazolol,carticaine, carvedilol, cephaeline, ciprofloxacin, clozapine,clobenzorex, clorprenaline, cyclopentamine, delapril, demexiptiline,denopamine, desipramine, desloratadine (clarinex), diclofenac,dimetofrine, dioxadrol, dobutamine, dopexamine, doripenem, dorzolamide,droprenilamine, duloxetine, eltoprazine, enalapril, enoxacin,epinephrine, ertapenem, esaprazole, esmolol, etoxadrol, fasudil,fendiline, fenethylline, fenfluramine, fenoldopam, fenoterol,fenproporex, flecainide, fluoxetine, formoterol, frovatriptan,gaboxadol, garenoxacin, gatifloxacin, grepafloxacin, hexoprenaline,imidapril, indalpine, indecainide, indeloxazine hydrochloride,isoxsuprine, ispronicline, labetalol, landiolol, lapatinib,levophacetoperane, lisinopril, lomefloxacin, lotrafiban, maprotiline,mecamylamine, mefloquine, mepindolol, meropenem, metapramine,metaproterenol, methoxyphenamine, dtmp (dextrorotary methylphenidate),methylphenidate, metipranolol, metoprolol, mitoxantrone, mivazerol,moexipril, moprolol, moxifloxacin, nebivolol, nifenalol, nipradilol,norfloxacin, nortriptyline, nylidrin, olanzapine, oxamniquine,oxprenolol, oxyfedrine, paroxetine, perhexiline, phenmetrazine,phenylephrine, phenylpropylmethylamine, pholedrine, picilorex,pimefylline, pindolol, pipemidic acid, piridocaine, practolol,pradofloxacin, pramipexole, pramiverin, prenalterol, prenylamine,prilocaine, procaterol, pronethalol, propafenone, propranolol,propylhexedrine, protokylol, protriptyline, pseudoephedrine, reboxetine,rasagiline, (r)-rasagiline, repinotan, reproterol, rimiterol, ritodrine,safinamide, salbutamol/albuterol, salmeterol, sarizotan, sertraline,silodosin, sotalol, soterenol, sparfloxacin, spirapril, sulfinalol,synephrine, tamsulosin, tebanicline, tianeptine, tirofiban, tretoquinol,trimetazidine, troxipide, varenicline (champix), vildagliptin,viloxazine, viquidil and xamoterol.

Preferred secondary amine-containing parent drugs from which prodrugs ofthe invention are derived include atenolol, atomoxetine, clozapine,desipramine, desloratadine (clarinex), diclofenac, doripenem,duloxetine, enalapril, ertapenem, fluoxetine, metoprolol, mecamylamine,meropenem, methylphenidate, dtmp (dextrorotary methylphenidate),olanzapine, paroxetine, pramipexole, rasagiline, ®-RASAGILINE,salbutamol/albuterol, tamsulosin, varenicline (hantix), andvildagliptin. In a more preferred embodiment, the secondaryamine-containing parent drug is selected from clozapine, duloxetine,mecamylamine, pramipexole, rasagiline, ®-RASAGILINE, and olanzapine.

In one embodiment, the parent drug moieties (APIs) are selected fromTable 14. In one embodiment, the prodrug is a compound of Formula LI orLI-A wherein API-1 and API-2 are selected from Table 14. In oneembodiment both API-1 and API-2 represent the same parent drug.

TABLE 14

In a more preferred embodiment, the invention relates to a prodrug ofolanzapine represented by formula:

In a more preferred embodiment, the invention relates to a prodrug ofolanzapine represented by formula:

In a preferred embodiment, the invention relates to a prodrug ofolanzapine represented by formula:

In a more preferred embodiment, the invention relates to a prodrug ofolanzapine represented by formula:

In a more preferred embodiment, the invention relates to a prodrug ofolanzapine represented by formula:

In a more preferred embodiment, the invention relates to a prodrug ofolanzapine represented by formula:

In a more preferred embodiment, the invention relates to a prodrug ofolanzapine represented by formula:

In a more preferred embodiment, the invention relates to a prodrug ofolanzapine represented by formula:

In a more preferred embodiment, the invention relates to a prodrug ofolanzapine represented by formula:

In a preferred embodiment, the invention relates to a prodrug ofolanzapine represented by formula:

Synthesis of Compounds

Generally, the compounds of the invention can be synthesized by themethod set forth in Schemes 3A and 3B where derivatization of olanzapineis illustrated.

Schemes 3A and 3B illustrate the synthesis of a compound of Formula LIby condensation of the parent drug, olanzapine, with chloromethylchloroformate, followed by condensation with a carboxylic acid.

DEFINITIONS

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

The terms “API”, “biologically active moiety”, “drug moiety” and “parentdrug moiety” are used interchangeably to refer to the structure of aparent drug molecule which is present in a prodrug conjugate of theinvention. As will be understood by one of skill in the art, in certainembodiments, linking the drug molecule to a carrier moiety proceeds viasubstitution at an oxygen or nitrogen atom of the parent drug moleculewith loss of a hydrogen atom. In these embodiments, the parent drugmoiety is the radical resulting from removal of the O—H or N—H hydrogenatom from the parent drug molecule. In certain embodiments, the carriermoiety is linked to the parent drug molecule without any loss of atomsfrom the parent drug molecule. In these embodiments, the parent drugmoiety includes the entire structure of the parent drug compound. Forexample, in case of a tertiary amine parent drug that is converted to aquaternary prodrug conjugate a loss of hydrogen from the parent drugdoesn't occur.

The term “aliphatic group” or “aliphatic” refers to a non-aromaticmoiety that may be saturated (e.g., single bond) or contain one or moreunits of unsaturation, e.g., double and/or triple bonds. An aliphaticgroup may be straight chained, branched or cyclic, contain carbon,hydrogen or, optionally, one or more heteroatoms and may be substitutedor unsubstituted. In addition to aliphatic hydrocarbon groups, aliphaticgroups include, for example, polyalkoxyalkyls, such as polyalkyleneglycols, polyamines, and polyimines, for example. Such aliphatic groupsmay be further substituted. It is understood that aliphatic groups mayinclude alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, and substituted or unsubstituted cycloalkyl groupsas described herein.

The term “acyl” refers to a carbonyl substituted with hydrogen, alkyl,partially saturated or fully saturated cycloalkyl, partially saturatedor fully saturated heterocycle, aryl, or heteroaryl. For example, acylincludes groups such as (C₁-C₆) alkanoyl (e.g., formyl, acetyl,propionyl, butyryl, valeryl, caproyl, t-butylacetyl, etc.),(C₃-C₆)cycloalkylcarbonyl (e.g., cyclopropylcarbonyl,cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.),heterocyclic carbonyl (e.g., pyrrolidinylcarbonyl,pyrrolid-2-one-5-carbonyl, piperidinylcarbonyl, piperazinylcarbonyl,tetrahydrofuranylcarbonyl, etc.), aroyl (e.g., benzoyl) and heteroaroyl(e.g., thiophenyl-2-carbonyl, thiophenyl-3-carbonyl, furanyl-2-carbonyl,furanyl-3-carbonyl, 1H-pyrroyl-2-carbonyl, 1H-pyrroyl-3-carbonyl,benzo[b]thiophenyl-2-carbonyl, etc.). In addition, the alkyl,cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl groupmay be any one of the groups described in the respective definitions.When indicated as being “optionally substituted”, the acyl group may beunsubstituted or optionally substituted with one or more substituents(typically, one to three substituents) independently selected from thegroup of substituents listed below in the definition for “substituted”or the alkyl, cycloalkyl, heterocycle, aryl and heteroaryl portion ofthe acyl group may be substituted as described above in the preferredand more preferred list of substituents, respectively.

The term “alkyl” is intended to include both branched and straightchain, substituted or unsubstituted saturated aliphatic hydrocarbonradicals/groups having the specified number of carbons. Preferred alkylgroups comprise about 1 to about 24 carbon atoms (“C₁-C₂₄”) preferablyabout 7 to about 24 carbon atoms (“C₇-C₂₄”), preferably about 8 to about24 carbon atoms (“C₈-C₂₄”), preferably about 9 to about 24 carbon atoms(“C₉-C₂₄”). Other preferred alkyl groups comprise at about 1 to about 8carbon atoms (“C₁-C₈”) such as about 1 to about 6 carbon atoms(“C₁-C₆”), or such as about 1 to about 3 carbon atoms (“C₁-C₃”).Examples of C₁-C₆ alkyl radicals include, but are not limited to,methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, n-pentyl,neopentyl and n-hexyl radicals.

The term “alkenyl” refers to linear or branched radicals having at leastone carbon-carbon double bond. Such radicals preferably contain fromabout two to about twenty-four carbon atoms (“C₂-C₂₄”) preferably about7 to about 24 carbon atoms (“C₇-C₂₄”), preferably about 8 to about 24carbon atoms (“C₈-C₂₄”), and preferably about 9 to about 24 carbon atoms(“C₉-C₂₄”). Other preferred alkenyl radicals are “lower alkenyl”radicals having two to about ten carbon atoms (“C₂-C₁₀”) such asethenyl, allyl, propenyl, butenyl and 4-methylbutenyl. Preferred loweralkenyl radicals include 2 to about 6 carbon atoms (“C₂-C₆”). The terms“alkenyl”, and “lower alkenyl”, embrace radicals having “cis” and“trans” orientations, or alternatively, “E” and “Z” orientations.

The term “alkynyl” refers to linear or branched radicals having at leastone carbon-carbon triple bond. Such radicals preferably contain fromabout two to about twenty-four carbon atoms (“C₂-C₂₄”) preferably about7 to about 24 carbon atoms (“C₇-C₂₄”), preferably about 8 to about 24carbon atoms (“C₈-C₂₄”), and preferably about 9 to about 24 carbon atoms(“C₉-C₂₄”). Other preferred alkynyl radicals are “lower alkynyl”radicals having two to about ten carbon atoms such as propargyl,1-propynyl, 2-propynyl, 1-butyne, 2-butynyl and 1-pentynyl. Preferredlower alkynyl radicals include 2 to about 6 carbon atoms (“C₂-C₆”).

The term “cycloalkyl” refers to saturated carbocyclic radicals havingthree to about twelve carbon atoms (“C₃-C₁₂”). The term “cycloalkyl”embraces saturated carbocyclic radicals having three to about twelvecarbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl.

The term “cycloalkenyl” refers to partially unsaturated carbocyclicradicals having three to twelve carbon atoms. Cycloalkenyl radicals thatare partially unsaturated carbocyclic radicals that contain two doublebonds (that may or may not be conjugated) can be called“cycloalkyldienyl”. More preferred cycloalkenyl radicals are “lowercycloalkenyl” radicals having four to about eight carbon atoms. Examplesof such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl.

The term “alkylene,” as used herein, refers to a divalent group derivedfrom a straight chain or branched saturated hydrocarbon chain having thespecified number of carbons atoms. Examples of alkylene groups include,but are not limited to, ethylene, propylene, butylene,3-methyl-pentylene, and 5-ethyl-hexylene.

The term “alkenylene,” as used herein, denotes a divalent group derivedfrom a straight chain or branched hydrocarbon moiety containing thespecified number of carbon atoms having at least one carbon-carbondouble bond. Alkenylene groups include, but are not limited to, forexample, ethenylene, 2-propenylene, 2-butenylene,1-methyl-2-buten-1-ylene, and the like.

The term “alkynylene,” as used herein, denotes a divalent group derivedfrom a straight chain or branched hydrocarbon moiety containing thespecified number of carbon atoms having at least one carbon-carbontriple bond. Representative alkynylene groups include, but are notlimited to, for example, propynylene, 1-butynylene,2-methyl-3-hexynylene, and the like.

The term “alkoxy” refers to linear or branched oxy-containing radicalseach having alkyl portions of one to about twenty-four carbon atoms or,preferably, one to about twelve carbon atoms. More preferred alkoxyradicals are “lower alkoxy” radicals having one to about ten carbonatoms and more preferably having one to about eight carbon atoms.Examples of such radicals include methoxy, ethoxy, propoxy, butoxy andtert-butoxy.

The term “alkoxyalkyl” refers to alkyl radicals having one or morealkoxy radicals attached to the alkyl radical, that is, to formmonoalkoxyalkyl and dialkoxyalkyl radicals.

The term “aryl”, alone or in combination, means a carbocyclic aromaticsystem containing one, two or three rings wherein such rings may beattached together in a pendent manner or may be fused. The term “aryl”embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl,indane and biphenyl.

The terms “heterocyclyl”, “heterocycle” “heterocyclic” or “heterocyclo”refer to saturated, partially unsaturated and unsaturatedheteroatom-containing ring-shaped radicals, which can also be called“heterocyclyl”, “heterocycloalkenyl” and “heteroaryl” correspondingly,where the heteroatoms may be selected from nitrogen, sulfur and oxygen.Examples of saturated heterocyclyl radicals include saturated 3 to6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms(e.g., pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.);saturated 3 to 6-membered heteromonocyclic group containing 1 to 2oxygen atoms and 1 to 3 nitrogen atoms (e.g., morpholinyl, etc.);saturated 3 to 6-membered heteromonocyclic group containing 1 to 2sulfur atoms and 1 to 3 nitrogen atoms (e.g., thiazolidinyl, etc.).Examples of partially unsaturated heterocyclyl radicals includedihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole.Heterocyclyl radicals may include a pentavalent nitrogen, such as intetrazolium and pyridinium radicals. The term “heterocycle” alsoembraces radicals where heterocyclyl radicals are fused with aryl orcycloalkyl radicals. Examples of such fused bicyclic radicals includebenzofuran, benzothiophene, and the like.

The term “heteroaryl” refers to unsaturated aromatic heterocyclylradicals. Examples of heteroaryl radicals include unsaturated 3 to 6membered heteromonocyclic group containing 1 to 4 nitrogen atoms, forexample, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.) tetrazolyl (e.g.,1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.; unsaturated condensedheterocyclyl group containing 1 to 5 nitrogen atoms, for example,indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g.,tetrazolo[1,5-b]pyridazinyl, etc.), etc.; unsaturated 3 to 6-memberedheteromonocyclic group containing an oxygen atom, for example, pyranyl,furyl, etc.; unsaturated 3 to 6-membered heteromonocyclic groupcontaining a sulfur atom, for example, thienyl, etc.; unsaturated 3- to6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl(e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.)etc.; unsaturated condensed heterocyclyl group containing 1 to 2 oxygenatoms and 1 to 3 nitrogen atoms (e.g., benzoxazolyl, benzoxadiazolyl,etc.); unsaturated 3 to 6-membered heteromonocyclic group containing 1to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl,thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g.,benzothiazolyl, benzothiadiazolyl, etc.) and the like.

The term “heterocycloalkyl” refers to heterocyclo-substituted alkylradicals. More preferred heterocycloalkyl radicals are “lowerheterocycloalkyl” radicals having one to six carbon atoms in theheterocyclo radical.

The term “alkylthio” refers to radicals containing a linear or branchedalkyl radical, of one to about ten carbon atoms attached to a divalentsulfur atom. Preferred alkylthio radicals have alkyl radicals of one toabout twenty-four carbon atoms or, preferably, one to about twelvecarbon atoms. More preferred alkylthio radicals have alkyl radicalswhich are “lower alkylthio” radicals having one to about ten carbonatoms. Most preferred are alkylthio radicals having lower alkyl radicalsof one to about eight carbon atoms. Examples of such lower alkylthioradicals include methylthio, ethylthio, propylthio, butylthio andhexylthio.

The terms “aralkyl” or “arylalkyl” refer to aryl-substituted alkylradicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl,and diphenylethyl.

The term “aryloxy” refers to aryl radicals attached through an oxygenatom to other radicals.

The terms “aralkoxy” or “arylalkoxy” refer to aralkyl radicals attachedthrough an oxygen atom to other radicals.

The term “aminoalkyl” refers to alkyl radicals substituted with aminoradicals. Preferred aminoalkyl radicals have alkyl radicals having aboutone to about twenty-four carbon atoms or, preferably, one to abouttwelve carbon atoms. More preferred aminoalkyl radicals are “loweraminoalkyl” that have alkyl radicals having one to about ten carbonatoms. Most preferred are aminoalkyl radicals having lower alkylradicals having one to eight carbon atoms. Examples of such radicalsinclude aminomethyl, aminoethyl, and the like.

The term “alkylamino” denotes amino groups which are substituted withone or two alkyl radicals. Preferred alkylamino radicals have alkylradicals having about one to about twenty carbon atoms or, preferably,one to about twelve carbon atoms. More preferred alkylamino radicals are“lower alkylamino” that have alkyl radicals having one to about tencarbon atoms. Most preferred are alkylamino radicals having lower alkylradicals having one to about eight carbon atoms. Suitable loweralkylamino may be monosubstituted N-alkylamino or disubstitutedN,N-alkylamino, such as N-methylamino, N-ethylamino, N,N-dimethylamino,N,N-diethylamino or the like.

The term “substituted” refers to the replacement of one or more hydrogenradicals in a given structure with the radical of a specifiedsubstituent including, but not limited to: halo, alkyl, alkenyl,alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl,arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl,alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl,arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino,trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl,arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl,alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl,carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl,heteroaryl, heterocyclic, and aliphatic. It is understood that thesubstituent may be further substituted.

For simplicity, chemical moieties that are defined and referred tothroughout can be univalent chemical moieties (e.g., alkyl, aryl, etc.)or multivalent moieties under the appropriate structural circumstancesclear to those skilled in the art. For example, an “alkyl” moiety can bereferred to a monovalent radical (e.g. CH₃—CH₂—), or in other instances,a bivalent linking moiety can be “alkyl,” in which case those skilled inthe art will understand the alkyl to be a divalent radical (e.g.,—CH₂—CH₂—), which is equivalent to the term “alkylene.” Similarly, incircumstances in which divalent moieties are required and are stated asbeing “alkoxy”, “alkylamino”, “aryloxy”, “alkylthio”, “aryl”,“heteroaryl”, “heterocyclic”, “alkyl” “alkenyl”, “alkynyl”, “aliphatic”,or “cycloalkyl”, those skilled in the art will understand that the termsalkoxy”, “alkylamino”, “aryloxy”, “alkylthio”, “aryl”, “heteroaryl”,“heterocyclic”, “alkyl”, “alkenyl”, “alkynyl”, “aliphatic”, or“cycloalkyl” refer to the corresponding divalent moiety.

The terms “halogen” or “halo” as used herein, refers to an atom selectedfrom fluorine, chlorine, bromine and iodine.

The terms “compound” “drug”, and “prodrug” as used herein all includepharmaceutically acceptable salts, co-crystals, solvates, hydrates,polymorphs, enantiomers, diastereoisomers, racemates and the like of thecompounds, drugs and prodrugs having the formulas as set forth herein.

Substituents indicated as attached through variable points ofattachments can be attached to any available position on the ringstructure.

As used herein, the term “effective amount of the subject compounds,”with respect to the subject method of treatment, refers to an amount ofthe subject compound which, when delivered as part of desired doseregimen, brings about management of the disease or disorder toclinically acceptable standards.

“Treatment” or “treating” refers to an approach for obtaining beneficialor desired clinical results in a patient. For purposes of thisinvention, beneficial or desired clinical results include, but are notlimited to, one or more of the following: alleviation of symptoms,diminishment of extent of a disease, stabilization (i.e., not worsening)of a state of disease, preventing spread (i.e., metastasis) of disease,preventing occurrence or recurrence of disease, delay or slowing ofdisease progression, amelioration of the disease state, and remission(whether partial or total).

The term “labile” as used herein refers to the capacity of the prodrugof the invention to undergo enzymatic and/or chemical cleavage in vivothereby forming the parent drug. As used herein the term “prodrug” meansa compounds as disclosed herein which is a labile derivative compound ofa parent drug which when administered to a patient in vivo becomescleaved by chemical and/or enzymatic hydrolysis thereby forming theparent drug such that a sufficient amount of the compound intended to bedelivered to the patient is available for its intended therapeutic usein a sustained release manner.

The term “dendrimer” refers to a class of highly branched, oftenspherical, macromolecular polymers that exhibit greater monodispersity(i.e., a smaller range of molecular weights, sizes, and shapes) thanlinear polymers of similar size. These three-dimensional oligomericstructures are prepared by reiterative reaction sequences starting froma core molecule (such as diaminobutane or ethylenediamine) that hasmultiple reactive groups. When monomer units, also having multiplereactive groups, are reacted with the core, the number of reactivegroups comprising the outer bounds of the dendrimer increases.Successive layers of monomer molecules may be added to the surface ofthe dendrimer, with the number of branches and reactive groups on thesurface increasing geometrically each time a layer is added. The numberof layers of monomer molecules in a dendrimer may be referred to as the“generation” of the dendrimer. The total number of reactive functionalgroups on a dendrimer's outer surface ultimately depends on the numberof reactive groups possessed by the core, the number of reactive groupspossessed by the monomers that are used to grow the dendrimer, and thegeneration of the dendrimer.

Pharmaceutical Compositions

The pharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of the present inventionformulated together with one or more pharmaceutically acceptablecarriers or excipients.

As used herein, the term “pharmaceutically acceptable carrier orexcipient” means a non-toxic, inert solid, semi-solid, gel or liquidfiller, diluent, encapsulating material or formulation auxiliary of anytype. Some examples of materials which can serve as pharmaceuticallyacceptable carriers are sugars such as lactose, glucose and sucrose;cyclodextrins such as alpha-(α), beta-(β) and gamma-(γ) cyclodextrins;starches such as corn starch and potato starch; cellulose and itsderivatives such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; powdered tragacanth; malt; gelatin; talc; excipientssuch as cocoa butter and suppository waxes; oils such as peanut oil,cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; glycols such as propylene glycol; esters such as ethyloleate and ethyl laurate; agar; buffering agents such as magnesiumhydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffersolutions, as well as other non-toxic compatible lubricants such assodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. In a preferredembodiment, administration is parenteral administration by injection.

The pharmaceutical compositions of this invention may contain anyconventional non-toxic pharmaceutically-acceptable carriers, adjuvantsor vehicles. In some cases, the pH of the formulation may be adjustedwith pharmaceutically acceptable acids, bases or buffers to enhance thestability of the formulated compound or its delivery form. The termparenteral as used herein includes subcutaneous, intracutaneous,intravenous, intramuscular, intraarticular, intraarterial,intrasynovial, intrasternal, intrathecal, intralesional and intracranialinjection or infusion techniques.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesuspension or emulsion, such as INTRALIPID®, LIPOSYN® or OMEGAVEN®, orsolution, in a nontoxic parenterally acceptable diluent or solvent, forexample, as a solution in 1,3-butanediol. INTRALIPID® is an intravenousfat emulsion containing 10-30% soybean oil, 1-10% egg yolkphospholipids, 1-10% glycerin and water. LIPOSYN® is also an intravenousfat emulsion containing 2-15% safflower oil, 2-15% soybean oil, 0.5-5%egg phosphatides 1-10% glycerin and water. OMEGAVEN® is an emulsion forinfusion containing about 5-25% fish oil, 0.5-10% egg phosphatides,1-10% glycerin and water. Among the acceptable vehicles and solventsthat may be employed are water, Ringer's solution, USP and isotonicsodium chloride solution. In addition, sterile, fixed oils areconventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil can be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid are used inthe preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

Additional sustained release in accordance with the invention may beaccomplished by the use of a liquid suspension of crystalline oramorphous material with poor water solubility. The rate of absorption ofthe drug then depends upon its rate of dissolution, which, in turn, maydepend upon crystal size and crystalline form. Alternatively, delayedabsorption of a parenterally administered drug form is accomplished bydissolving or suspending the drug in an oil vehicle. Injectable depotforms are made by forming microencapsule matrices of the drug inbiodegradable polymers such as polylactide-polyglycolide. Depending uponthe ratio of drug to polymer and the nature of the particular polymeremployed, the rate of drug release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping the drugin liposomes or microemulsions that are compatible with body tissues.

In one preferred embodiment, the formulation provides a sustainedrelease delivery system that is capable of minimizing the exposure ofthe prodrug to water. This can be accomplished by formulating theprodrug with a sustained release delivery system that is a polymericmatrix capable of minimizing the diffusion of water into the matrix.Suitable polymers comprising the matrix include polylactide (PLA)polymers and the lactide/glycolide (PLGA) co-polymers.

Alternatively, the sustained release delivery system may comprisepoly-anionic molecules or resins that are suitable for injection or oraldelivery. Suitable polyanionic molecules include cyclodextrins andpolysulfonates formulated to form a poorly soluble mass that minimizesexposure of the prodrug to water and from which the prodrug slowlyleaves.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or: a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

For pulmonary delivery, a therapeutic composition of the invention isformulated and administered to the patient in solid or liquidparticulate form by direct administration e.g., inhalation into therespiratory system. Solid or liquid particulate forms of the activecompound prepared for practicing the present invention include particlesof respirable size: that is, particles of a size sufficiently small topass through the mouth and larynx upon inhalation and into the bronchiand alveoli of the lungs. Delivery of aerosolized therapeutics,particularly aerosolized antibiotics, is known in the art (see, forexample U.S. Pat. No. 5,767,068 to VanDevanter et al., U.S. Pat. No.5,508,269 to Smith et al., and WO 98/43650 by Montgomery, all of whichare incorporated herein by reference). A discussion of pulmonarydelivery of antibiotics is also found in U.S. Pat. No. 6,014,969,incorporated herein by reference.

By a “therapeutically effective amount” of a prodrug compound of theinvention is meant an amount of the compound which confers a therapeuticeffect on the treated subject, at a reasonable benefit/risk ratioapplicable to any medical treatment. The therapeutic effect may beobjective (i.e., measurable by some test or marker) or subjective (i.e.,subject gives an indication of or feels an effect).

In accordance with the invention, the therapeutically effective amountof a prodrug of the invention is typically based on the targettherapeutic amount of the parent drug. Information regarding dosing andfrequency of dosing is readily available for many parent drugs fromwhich the prodrugs of the invention are derived and the targettherapeutic amount can be calculated for each prodrug of the invention.In accordance with the invention, the same dose of a prodrug of theinvention provides a longer duration of therapeutic effect as comparedto the parent drug. Thus if a single dose of the parent drug provides 12hours of therapeutic effectiveness, a prodrug of that same parent drugin accordance with the invention that provides therapeutic effectivenessfor greater than 12 hours will be considered to achieve a “sustainedrelease”.

The precise dose of a prodrug of the invention depends upon severalfactors including the nature and dose of the parent drug and thechemical characteristics of the prodrug moiety linked to the parentdrug. Ultimately, the effective dose and dose frequency of a prodrug ofthe invention will be decided by the attending physician within thescope of sound medical judgment. The specific therapeutically effectivedose level and dose frequency for any particular patient will dependupon a variety of factors including the disorder being treated and theseverity of the disorder; the activity of the specific compoundemployed; the specific composition employed; the age, body weight,general health, sex and diet of the patient; the time of administration,route of administration, and rate of excretion of the specific compoundemployed; the duration of the treatment; drugs used in combination orcontemporaneously with the specific compound employed; and like factorswell known in the medical arts.

Examples STEP 1: Synthesis of7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-1-(hydroxymethyl)-3,4-dihydroquinolin-2(1H)-one

Procedure:

A mixture of Aripiprazole (5.2 g, 0.012 mol), triethylamine (0.25 mL,0.0018 mol), 37% aqueous formaldehyde solution (18.5 mL) anddimethylformamide (50 mL) was heated at 80° C. for 48 hours. After 48hours the reaction mixture was cooled to ambient temperature, dilutedwith ethyl acetate (200 mL) and washed with water (2×200 mL) and brine(2×200 mL). The organic phase was dried with sodium sulphate, filteredand concentrated in vacuo to give hemi-aminal as a white solid [5.6 g,containing 43% Aripiprazole and 56% hemi-aminal (as per LCMS analysis)].

Synthesis of Bis((7-(4-(4-(2,3-dichlorophenyl) piperazin-1-yl)butoxy)-2oxo-3,4-dihydroquinolin-1(2H)-yl)methyl) decanedioate

Procedure:

A solution of Step-1 reaction mixture (1.0 g, 0.0021 mol) indichloromethane (20 mL) was stirred at 25° C. under nitrogen atmosphere.Triethylamine (1.45 mL, 0.0105 mol) was added drop wise to the abovesolution at 25° C. and the resulting reaction mixture was allowed tostir at the same temperature for next 10 minutes. After 10 minutes asolution of sebacoyl chloride in dichloromethane (0.223 mL, 0.00105 molsebacoyl chloride in 2.2 mL dichloromethane) was added drop wise to theabove reaction mixture at 25° C. The resulting clear reaction mixturewas warmed to 45° C. whereby it was allowed to stir for next 2 hours.The reaction mixture was partitioned between dichloromethane (100 mL)and water (200 mL) and the aqueous layer was extracted withdichloromethane (2×100 mL). The combined organic fractions were washedwith brine (100 mL), dried over sodium sulphate, filtered andconcentrated in vacuo. The product was purified by flash chromatographyusing dichloromethane: methanol as mobile phase and the desired producteluted at around 1.5% methanol in dichloromethane to provide Compound-6[0.3 g, 22% yield].

¹H NMR (DMSO, 400 MHz) δ 1.171 (s, 8H), 1.44-1.49 (m, 4H), 1.56-1.61 (m,4H), 1.69-1.76 (m, 4H), 2.29 (t, 4H), 2.37 (t, 4H), 2.57 (t, 4H), 2.80(t, 4H), 2.95 (broad s, 8H), 3.35 (broad s, 8H), 3.97 (t, 4H), 5.86(broad s, 4H), 6.63-6.65 (m, 4H), 7.09-7.14 (m, 4H), 7.27-7.31 (m, 4H);m/z (M⁺H) 1123.

Synthesis of Compound-7: Bis((7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl) butoxy)-2oxo-3,4-dihydroquinolin-1(2H)-yl)methyl)dodecanedioate

Procedure:

A solution of Step-1 (1.0 g, 0.0021 mol) in dichloromethane (20 mL) wasstirred at 25° C. under nitrogen atmosphere. Triethylamine (1.45 mL,0.0105 mol) was added drop wise to the above solution at 25° C. and theresulting reaction mixture was allowed to stir at the same temperaturefor next 10 minutes. After 10 minutes a solution of dodecandioyldichloride in dichloromethane (0.280 g, 0.00105 mol dodecandioyldichloride in 2.5 mL dichloromethane) was added drop wise to the abovereaction mixture at 25° C. The resulting clear reaction mixture waswarmed to 45° C. whereby it was allowed to stir for next 2 hours. Thereaction mixture was partitioned between dichloromethane (100 mL) andwater (200 mL) and the aqueous layer was extracted with dichloromethane(2×100 mL). The combined organic were washed with brine (100 mL), driedover sodium sulphate, filtered and concentrated in vacuo. The productwas purified by flash chromatography using dichloromethane: methanol asmobile phase and the desired product eluted at around 1.5% methanol indichloromethane. Distillation of the product fractions providedCompound-7 [0.160 g, 11% yield].

¹H NMR (DMSO, 400 MHz) δ 1.16-1.18 (s, 12H), 1.47-1.50 (m, 4H),1.57-1.62 (m, 4H), 1.71-1.75 (m, 4H), 2.28-2.32 (t, 4H), 2.38 (t, 4H),2.57 (t, 4H), 2.80 (t, 4H), 2.95 (broad s, 8H), 3.34 (broad s, 8H), 3.97(t, 4H), 5.86 (broad s, 4H), 6.63-6.65 (m, 4H), 7.10-7.15 (m, 4H),7.28-7.31 (m, 4H); m/z (M⁺H) 1149.7.

Synthesis of Compound-8 Synthesis of Tetradecandioyl Dichloride

Oxalyl chloride (1.35 mL, 0.015 mol) was added drop wise to a solutionof Tetradecandioyl dichloride (1.0 g, 0.0039 mol) in dichloromethane at25° C. After the addition was completed, the reaction mixture wasstirred at same temperature for 2 hours, the reaction mixture waspartitioned between dichloromethane (100 mL) and water (200 mL), theaqueous layer was extracted with dichloromethane (2×100 mL). Thecombined organic extracts were washed with brine (200 mL), dried oversodium sulphate filtered and concentrated in vacuo to provide thedesired product (0.9 g, 90% yield) as a colorless liquid which was useddirectly for the next step without further purification.

Synthesis of Bis((7-(4-(4-(2,3-dichlorophenyl) piperazin-1-yl)butoxy)-2oxo-3,4-dihydroquinolin-1(2H)-yl)methyl)tetradecanedioate

A solution of Step-1 (1.0 g, 0.0021 mol) in dichloromethane (20 mL) wasstirred at 25° C. under nitrogen atmosphere. Triethylamine (1.45 mL g,0.0105 mol) was added drop wise to the above solution at 25° C. and theresulting reaction mixture was allowed to stir at the same temperaturefor next 10 minutes. After 10 minutes a solution of tetradecandioyldichloride in dichloromethane (0.308 g, 0.00105 mol tetradecandioyldichloride in 3.0 mL dichloromethane) was added drop wise to the abovereaction mixture at 25° C. The resulting clear reaction mixture waswarmed to 45° C. whereby it was allowed to stir for next 2 hours. Thereaction mixture was partitioned between dichloromethane (100 mL) andwater (200 mL) and the aqueous layer was extracted with dichloromethane(2×100 mL). The combined organic were washed with brine (200 mL), driedover sodium sulphate, filtered and concentrated in vacuo. The productwas purified by flash chromatography using dichloromethane: methanol asmobile phase and the desired product eluted at around 1.8% methanol indichloromethane to provide Compound-8 [0.170 g, 12% yield].

¹H NMR (DMSO, 400 MHz) δ 1.16-1.24 (m 18H), 1.47-1.51 (m, 4H), 1.57-1.62(m, 4H), 1.70-1.75 (m, 4H), 2.30 (t, 4H), 2.38 (t, 4H), 2.57 (t, 4H),2.80 (t, 4H), 2.96 (broad s, 8H), 3.34 (broad s, 8H), 3.97 (t, 4H), 5.86(broad s, 4H), 6.654 (m, 4H), 7.10-7.15 (m, 4H), 7.27-7.31 (m, 4H); m/z(M⁺H) 1177.9.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1-15. (canceled)
 16. A prodrug conjugate, having the formula:

wherein each R₅₀, R₅₁, R₅₂, R₅₃, R₅₄ and R₅₅ is independently selectedfrom hydrogen, halogen, —OR₁₀, —SR₁₀, —NR₁₀R₁₁—, optionally substitutedaliphatic, optionally substituted aryl or aryl or optionally substitutedheterocyclyl; alternatively, two or more R₅₀, R₅₁, R₅₂, R₅₃, R₅₄ and R₅₅together form an optionally substituted ring; each R₁₀₀, R₁₀₁, R₁₀₂, andR₁₀₃ are independently selected from absent, hydrogen, halogen, —OR₁₀,—SR₁₀, —NR₁₀R₁₁—, optionally substituted aliphatic, optionallysubstituted aryl or optionally substituted heterocyclyl; alternatively,two R₁₀₀, and R₁₀₁ together form an optionally substituted ring; h is3or 4; X₁₀₀ is —CH— or —N—; C1 is a carrier moiety; and, X₂ is selectedfrom direct bond, O, S or NR₂₀.
 17. A prodrug conjugate of claim 16,having the formula:

wherein n is selected from 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and
 30. 18. A prodrugconjugate, having the formula:

wherein Cy₂ is an optionally substituted heterocyclic ring; and X₅ isselected from absent, —S—, —O—, —S(O)—, —S(O)₂—, —N(R₁₀)—, —C(O)—,—C(OR₁₀)(R₁₁)—, —[C(R₁₀)(R₁₁)]_(v)—, —O[C(R₁₀)(R₁₁)]_(v)—,—O[C(R₁₀)(R₁₁)]_(v)O—, —S[C(R₁₀)(R₁₁)]_(v)O—, —NR₁₂[C(R₁₀)(R₁₁)]_(v)O—,—NR₁₂[C(R₁₀)(R₁₁)]_(v)S—, —S[C(R₁₀)(R₁₁)]_(v)—, —C(O)[C(R₁₀)(R₁₁)]_(v)—,and —C(R₁₀)(R₁₁)═C(R₁₀)(R₁₁)—; wherein v is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9or 10; C1 is a carrier moiety; and, X₂ is selected from direct bond, O,S or NR₂₀.
 19. The prodrug conjugate, having the formula:

wherein A₁, B₁ and E₁ together with the nitrogen they are attached toform a tertiary amine containing first biologically active molecule; A₂,B₂ and E₂ together with the nitrogen they are attached to form atertiary amine containing second biologically active molecule; X is apharmaceutically acceptable counterion; X₁ is selected from O or S; X₂is selected from direct bond, O, S or NR₂₀ wherein R₂₀ is selected fromhydrogen, halogen, aliphatic, substituted aliphatic, aryl or substitutedaryl; and C1 represents a carrier group. 20-27. (canceled)
 28. Theprodrug conjugate, having the formula:

wherein API-1 is a biologically active moiety; and API-2 is abiologically active moiety and is the same or different from API-1; andAPI-3 is a biologically active moiety and is the same or different fromAPI-1 and API-2.
 29. (canceled)
 30. A method for sustained delivery of aparent drug to a patient comprising administering a prodrug compound ofclaim 1, wherein upon administration to the patient, release of theparent drug from the prodrug is sustained. 31-33. (canceled)
 34. Amethod of synthesizing a compound of formula I, IA or IB comprising thesteps of reacting a dicarboxylic acid containing compound with thionylchloride followed by reacting with formaldehyde or trioxane to yieldchloromethyl ester which is reacted with a biologically active compoundto give said compound of formula I, IA, IB. 35-80. (canceled)